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CARDIOVASCULAR

In Vivo Cardiac Electrophysiologic Effects of a Novel Diphenylphosphine Oxide I_Kur Blocker, (2-Isopropyl-5-methylcyclohexyl) Diphenylphosphine Oxide, in Rat and Nonhuman Primate

Departments of Stroke (C.P.R., H.K.C., J.J.L.), Medicinal Chemistry (A.A.W.), and Molecular Endocrinology (C.L.A.), Merck Research Laboratories, West Point, Pennsylvania

The voltage-gated potassium channel, Kv1.5, which underlies the ultrarapid delayed rectifier current, I_Kur, is reported to be enriched in human atrium versus ventricle, and has been proposed as a target for novel atrial antiarrhythmic therapy. The administration of the novel I_Kur blocker (2-isopropyl-5-methyl-cyclohexyl) diphenylphosphine oxide (DPO-1) (0.06, 0.2, and 0.6 mg/kg/min i.v. x 20 min; total doses 1.2, 4.0, and 12.0 mg/kg, respectively) to rat, which exhibits I_Kur in both atria and ventricle, elicited significant, dose-dependent increases in atrial and ventricular refractory period (9-42%) at all doses tested, with no changes in cardiac rate or indices of cardiac conduction. Plasma levels achieved in rat at the end of the three infusions were 1.1, 4.1, and 7.7 µM. Reverse transcription-polymerase chain reaction analysis of African green monkey atria and ventricle demonstrated an atrial preferential distribution of Kv1.5 transcript. The administration of DPO-1 (1.0, 3.0, and 10.0 mg/kg i.v.; 5-min infusions) to African green monkey elicited significant increases in atrial refractoriness (approximately 15% increase at the 10.0 mg/kg dose), with no change in ventricular refractory period, ECG intervals, heart rate, or blood pressure. Plasma levels of DPO-1 achieved in African green monkey were 0.58, 1.12, and 5.43 µM. The concordance of effect of DPO-1 on myocardial refractoriness with distribution of Kv1.5 in these two species is consistent with the I_Kur selectivity of DPO-1 in vivo. Moreover, the selective increase in atrial refractoriness in primate supports the concept of I_Kur blockade as an approach for the development of atrial-specific antiarrhythmic agents.

Address correspondence to: Dr. Joseph J. Lynch, WP46-300, Merck Research Laboratories, West Point, PA 19486. E-mail: joseph_lynch{at}merck.com

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